This proposal is a competing continuation of the NIH grant R01 NS051335. The long term goal is to produce polypeptides that could cross the blood-brain barrier (BBB) and so be developed as central nervous system (CNS) therapeutics. The goal is achieved by modification of polypeptides with Pluronic copolymers (poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)). The studies have focused on leptin, a candidate for the treatment of epidemic obesity. Leptin failure is mostly due to peripheral resistance - a loss of its ability to cross the BBB necessary to reach its receptors in the arcuate nucleus of the hypothalamus. The previous work produced a conjugate of leptin with Pluronic P85 that is centrally active, has a long half-life in blood, is enzymatically resistant, crosses the BBB by a non-saturable mechanism independently of the leptin transporter, and can exert effects on feeding and body weight after peripheral administration. This proposal will: 1). optimize modifications to produce superior leptin analogs with maximal BBB permeability, improved half-life in blood and high enzymatic resistance in brain and blood; 2). identify mechanisms underlying enhanced permeability of leptin analogs in BBB; 3). determine the permeability of modified leptin analogs across the BBB to select the best analogs for activity testing; and 4) determine the biological activity after intravenous injection of the best leptin analogs 3 in leptin sensitive (ob/ob) and leptin resistant (dietary obese) mouse models of obesity. Analogs completing this development will be a) active in brain, b) have favorable pharmacokinetics, c) be able to cross the BBB in obese mice, and d) reverse obesity after iv injection. Such analogs are candidates for clinical trials in human obesity.